EP1294446A2 - Composes polycycliques modifies d'alkyle ether ayant un phenol terminal et utilisations pour la protection de cellules - Google Patents

Composes polycycliques modifies d'alkyle ether ayant un phenol terminal et utilisations pour la protection de cellules

Info

Publication number
EP1294446A2
EP1294446A2 EP01955052A EP01955052A EP1294446A2 EP 1294446 A2 EP1294446 A2 EP 1294446A2 EP 01955052 A EP01955052 A EP 01955052A EP 01955052 A EP01955052 A EP 01955052A EP 1294446 A2 EP1294446 A2 EP 1294446A2
Authority
EP
European Patent Office
Prior art keywords
compound
cells
ring
group
alkyl ether
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01955052A
Other languages
German (de)
English (en)
Inventor
Laszlo Prokai
James W. Simpkins
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Florida
University of Florida Research Foundation Inc
Original Assignee
University of Florida
University of Florida Research Foundation Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Florida, University of Florida Research Foundation Inc filed Critical University of Florida
Publication of EP1294446A2 publication Critical patent/EP1294446A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents

Definitions

  • the present invention relates to methods and compositions to achieve a cytoprotective effect concerning a polycyclic compound with a phenol group at a first end and a carbon ring at a second end in which the hydroxy group on the carbon ring has been substituted by an alkyl ether group.
  • the naturally occurring hormone 17 ⁇ -estradiol plays a pivotal role in sexual reproduction in humans and other mammals. It is believed that this estrogenic activity is orchestrated through the binding of estrogen receptors on the surface of target cells (Gridley et al. (1998) Vol. 54, pp. 874-880). Estrogen compounds including 17 ⁇ -estradiol have also been shown to have neuroprotective activity (US 5,554,601).
  • cytoprotective activity has been demonstrated for estrogen compounds that have little or no estrogenic activity and in addition have low or negligable binding affinity for the estrogen receptor (US 5,843,934).
  • An important functional group in these molecules that determine cytoprotection is the presence of a terminal phenolic group. This observation led to the realization that polycyclic compounds had neuroprotective activity contingent on the presence of a terminal phenol group. (US 5,859,001, 6,197,833) (Bishop et al. (1994) Mol. Cell. Neurosci, Vol. 5, pp. 303-308; Green et al. (1997) J. Steroid Biochem. Mol. BioL, Vol. 63, pp. 229-235).
  • cytoprotective activity has numerous uses in protecting cells in vivo and in vitro from degeneration that may occur through disease, trauma or aging. Treatment based on cytoprotection can lead to the slowing of progression of degeneration and postpone the onset of symptoms associated with degeneration. It is desirable therefore, to identify improvements in cytoprotective compounds that might enhance their bioactivity.
  • a first embodiment of the invention provides a cytoprotective compound that includes a polycyclic compound optionally having two, three or four carbon rings, the compound also having a first end and a second end wherein a phenol group is located at the first end and a terminal carbon ring is located at the second end, the terminal carbon ring having an alkyl ether functional group, the alkyl portion of which having a formula C n H 2n+2 wherein n is at least 3 and less than 20.
  • the carbon ring at the second end is a D ring in a four ring compound which may be an estrogen.
  • the four ring estrogen compound may include an alkyl ether group in an alpha or beta orientation.
  • the alkyl ether functional group can include any of a long chain saturated alkyl, a long chain unsaturated alkyl, or a cycloalkyl group.
  • the cytoprotective compound may be a 17-butoxyestra 1,3,5(10) triene-3-ol, 17-pentoxyestra 1, 3, 5 (10) triene-3-ol a 17-hexoxyestra 1,3,5(10) triene-3-ol, a 17 septoxyestra 1,3,5(10) triene-3-ol, or a 17-octyloxyestra 1,3,5(10) triene-3- ol.
  • the cytoprotective compound includes an estrogen compound having a terminal phenol group at a first end of the compound and a carbon ring at a second end of the compound, the carbon ring at the second end having an alkyl ether functional group wherein the alkyl group has a formula C n H 2n+2 wherein n is at least 3 and less than 20.
  • a pharmaceutical formulation in a third embodiment of the invention, includes a cytoprotection effective dose of a polycyclic compound having a phenolic ring at a first terminal position, optionally any of one, two or three additional ring structures and an alkyl ether functional group on a carbon ring in a second terminal position.
  • a method for retarding the development of a degenerative condition associated with a population of cells in a subject that includes administering to the subject predisposed to the degenerative condition, an effective amount of a polycyclic phenolic compound in a physiologically acceptable formulation, the polycyclic phenolic compound having a phenol located at a first terminal position, optionally any of one, two or three additional ring structures; the compound having an alkyl ester located on a carbon ring at a second terminal position, the compound retarding the development of the degenerative condition.
  • the method may utilize any of the alkyl ether compounds described herein including four ring compounds with an alkyl ether on carbon 17 of the D ring in an alpha or beta orientation and may further include enantiomers, diastomers, salts, derivatives and analogs.
  • the population of cells or tissues may be selected from stem cells, blood cells, epithelial cells, stromal cells including connective tissue cells, neuronal cells, muscle tissue cells, endocrine tissue cells, whole organ cells, bone cells, eye cells, skin cells, reproductive tract cells and urinary tract cells.
  • the degenerative condition may include cardiac, eye, bone, neurodegenerative or ischemic degeneration.
  • a method for synthesizing an estrogen compound having a phenolic A ring and an alkyl ether functional group on carbon 17, that includes: protecting -OH on the phenolic A ring; alkylating the 17-OH with an alkylating agent in the presence of a strong base; removing the protecting group from -OH on the phenolic A ring; and purifying the 17- alkyl ether estrogen compound.
  • the - OH may be on the carbon 3-position and the 17-OH may be in an alpha or beta position.
  • the alkylating agent may be selected from a group consisting of an alkyl halide, a dialkyl sulfate and an alkyl tosylate.
  • the phenolic-OH may be treated with a base resistant protecting group such as tert-butyl, methoxymethyl and 9-anthrylmethyl.
  • the protecting group may be removable by acid hydrolysis, catalytic hydrogenolysis where the hydrogenolysis may include CF 3 COOH or by catalytic transfer hydrogenation which may use ammonium formate.
  • the strong base of the method may include sodium hydride.
  • a method for treating a subject having a degenerative disorder comprising: obtaining at least one 17-O-alkyl ether of estrogen in a pharmaceutical formulation; and administering an effective dose of the 17-O- alkyl ether of estrogen to the subject so as to treat the degenerative disorder.
  • a method for conferring cytoprotection of a population of cells that includes providing an 17 ⁇ -O-alkyl ether of an estrogen compound; and administering the compound in an effective dose to the population of cells so as to confer cytoprotection on the population of cells.
  • All embodiments directed to methods include the use of any of the alkyl ether compounds described herein Brief Description of the Drawings
  • Figure 1 shows the structure of the alkyl ether of estradiol.
  • Figure 2 shows the synthesis of 17-alkyl ether of estradiol.
  • Figure 3 is an ORTEP plot of the X-ray crystal structure of 17-O-butylated 17 ⁇ -estradiol (4 Thermal ellipsoids are shown at the 30% probability level.
  • Figure 4 shows a graphical representation of cell viability, where the cells are HT-22 cell cultures after giutamate exposure (20 mM) (a) following treatment with estradiol and its 17 ⁇ -alkyl ethers (4a-4f), and 3-butyl estradiol (5b as a typical representative of the 3-alkyl ethers).
  • Estrogen compound is defined here and in the claims as any of the structures described in the 11 th edition of "Steroids” from Steraloids, hie. Wilton, NH, here incorporated by reference. Included in this definition are non-steroidal estrogens described in the aforementioned reference. Other estrogen compounds included in this definition are cyclopenantophenanthrene compounds, estrogen derivatives, estrogen metabolites and estrogen precursors as well as those molecules capable of binding cell associated estrogen receptor as well as other molecules where the result of binding specifically triggers a characterized estrogen effect. Assumed as included in this definition but more explicitly stated, are isomers, diasteromers and enantiomers of the aforementioned, as well as mixtures of more than one estrogen.
  • cytoprotective effect is a measurable positive effect on the survival of cells that would otherwise die without an intervention.
  • Treatment of a disorder in a patient with a cytoprotective compound may be characterized as, but is not limited to, a slowing of progression of a disorder and optionally slowing of the development of symptoms than would otherwise occur in the absence of the compound.
  • Alkyl ether functional group on the carbon ring at the second end includes locating the alkyl ether functional group on any available carbon in the ring for example, carbon- 15, - 16 or -17.
  • terminal phenol group includes a carbon ring with an OH- group on any of carbons 2, 3 or 4.
  • Alkyl ether functional group on carbon 17 of the D ring refers unless specified otherwise to 17 ⁇ -, 17 ⁇ -, enantiomers of the four ring compound, salts, derivatives and analogs thereof.
  • a 17-alkylestra-l, 3,5(10) triene-3-ol refers to any of the 17- ⁇ or 17- ⁇ diesteromer, and the enantiomers of the compound, salts, derivatives and analogs thereof.
  • 17- refers to l7 ⁇ - or l7 ⁇ -.
  • novel modifications of known compounds that have improved cytoprotective activity when compared with the unmodified forms.
  • the novel compounds are polycyclic compounds with a terminal phenol group that have been modified in such a way as to increase the lipophilicity of the compounds for improved uptake by target cells thereby improving the cytoprotective effect of the compounds while maintaining the terminal phenol group.
  • Polycyclic compounds with a terminal phenol group prior to modification with an alkyl ether as described below include those compounds listed in US patent 6,197,833 herein incorporated by reference.
  • a limitation on the length of the alkyl ether resides in the solubility of the compound in solvents suitable for delivery of the compound to a subject by an appropriate route of delivery selected to achieve either acute or chronic administration. Examples of solvents are provided below.
  • the alkyl ether modification may further include cyclical alkyl ethers including cyclohexyl and cyclopentyl derivatives.
  • a method for making alkyl ethers of polycyclic compounds having a terminal phenol group is provided in Example 1.
  • the hydroxyl group on the terminal phenol is protected when the compound is reacted with an alkylating agent by a protecting group.
  • the protecting group is subsequently removed.
  • the alkylating agent may be selected from a group consisting of an alkyl halide, a dialkyl sulfate and an alkyl tosylate.
  • the phenolic-OH may be treated with a base resistant protecting group such as tert-butyl, methoxymethyl and 9-anthrylmethyl.
  • the protecting group may be removed by acid hydrolysis, catalytic hydrogenolysis where the hydrogenolysis may include CF 3 COOH or by catalytic transfer hydrogenation which may use ammonium formate.
  • the strong base of the method may include
  • an alkyl ether substituted 17- ⁇ estradiol is shown schematically in Figure 1.
  • the synthetic pathway for making 17-alkyl ether of estradiol is shown in Figure 2 with a crystallographic structure of 17-O-butylated 17- ⁇ estradiol in Figure 3.
  • the cytoprotection provided by alkyl ether compounds as described has been demonstrated in HT22 assays. ( Figure 4) The observed cytoprotective effect is independent of estrogenic normal activity. Cytoprotective activity using these compounds is not limited to HT22 cells but is applicable to different cell populations and tissues found in a subject and present in vivo and in vitro regardless of whether those cells carried an estrogen receptor or not.
  • the experimental models for measuring cytoprotection have become established using a range of cell cultures such as HT22, (described below in the Example 2) SK-N-SH (American Type Culture Collection, Rockville, MD) described in US Patent 5,554,601, erythrocytes and muscle cells and in in vivo animal models.
  • Experimental animals such as rats have been described in which a traumatic event such as ovariectomy itself or additional insult such as an arterial occlusion is generated in ovariectomized and non-ovariectomized animals. (US Patents 5,554,601, and 5,859,001).
  • the treated and non-treated rats are then measured for the cytoprotective effect afforded by a range of doses of the compound administered to the animal subject.
  • the cytoprotective compounds described herein can be used in effective doses to treat patients with acute or chronic degenerative disorders.
  • acute degenerative disorders include: tissue ischemic events (US patent 5,877,169, herein incorporated by reference), for example, cerebrovascular disease, subarachnoid hemorrhage or trauma, prevention of ischemia reperfusion injury, prevention of ischemia reperfusion injury in the setting of resuscitation from hypovolemic shock, renal ischemia, myocardial infarction, angina and cardiac ischemia, endothelial inflammation, and cardiotoxicity associated with administration of anti -cancer compositions.
  • effective doses of the cytoprotective compounds may be beneficial in treating osteoporosis.
  • the compounds may be used to protect cells in graft tissue during transplantation.
  • the compounds may be used to protect aging skin and skin damaged by cytotoxic events either in a cosmetic formulation or as a therapeutic agent.
  • the compounds may be used to protect against vascular degeneration associated with diabetes.
  • Graft cells include those cells, tissues or organs obtained from a donor by transplantation into a recipient, where the graft cells may be derived from human subjects or from animals and may be transplanted from one subject back into the same subject or from one subject (the donor) into another subject (the recipient) for improving the health of the recipient.
  • the donor subject can be a living subject, fetus or a recently deceased subject.
  • the grafts cells and tissues include stem cells, blood cells, bone marrow cells, placental cells, sperm and ova and may further include heart, lungs, corneal tissue or fetal tissue. Accordingly, the compounds described herein may be beneficial in protecting graft cells from damage resulting from oxidative stress.
  • the cytoprotective compounds described herein can be used to protect neurons from severe degeneration and is an important aspect of treatment for patients with acute or chronic neurodegenerative disorders.
  • chronic disease include Alzheimer's disease. (US 5,554,601 herein incorporated by reference), Parkinson's disease, Huntingdon's disease, AIDS dementia, Wernicke-Korsakoff s related dementia (alcohol induced dementia), age related dementia, age associated memory impairment, brain cell loss due to any of the following: head trauma, stroke, myocardial infarction, hypoglycemia, ischemia, anoxia, hyopoxia, cerebral edema, arteriosclerosis, diabetic neuropathy, hematoma and epilepsy, spinal cord cell loss due to any of the conditions listed under brain cell loss; and peripheral neuropathy.
  • degenerative diseases, disorders and conditions that may be treatable by a cytoprotective agent include: various bone disorders including osteoporosis, osteomyelitis, ischemic bone disease, fibrous dysplasia, rickets, Gushing' s syndrome and osteoarthritis, other types of arthritis and conditions of connective tissue and cartilage degeneration including rheumatoid, psoriatic and infectious arthritis, various infectious diseases, muscle wasting disorders such as muscular dystrophy, skin disorders such as dermatitis, eczema, psoriasis and skin aging, degenerative disorders of the eye including macular degeneration and retinal degeneration, disorder of the ear such as otosclerosis, impaired wound healing, various diseases and conditions of the heart including cardiac ischemia, myocardial infarction, chronic or acute heart failure, cardiac dysrhymias, artrial fibrillation, paroxymial tachycardia, ventricular fibrillation and congestive heart failure, circulatory disorders including athe
  • compositions may be used for protecting cells including any of the below listed cells or tissues and for treatment of disorders including any of the aforementioned degenerative conditions.
  • cells that may be protected by the compounds include: stem cells, blood cells, epithelial cells, stromal cells including connective tissue cells, neuronal cells, muscle tissue cells, endocrine tissue cells, whole organ cells, bone cells, skin cells, eye cells, reproductive tract cells and urinary tract cells and tissues that include more than one cell type.
  • Tissues that are protected by the method of the invention may be derived from children, adult or fetal tissue and include, but are not limited to blood and all of its components, including erythrocytes, leukocytes, platelets, serum, central nervous tissue, including brain and spinal cord tissue, neurons, and glia; peripheral nervous tissue, including ganglia, posterior pituitary gland, adrenal medulla, and pineal; connective tissue, including skin, ligaments, tendons, and fibroblasts; muscle tissue, including skeletal, smooth and cardiac tissues or the cells therefrom; endocrine tissue, including anterior pituitary gland, thyroid gland, parathyroid gland, adrenal cortex, pancreas and its subparts, testes, ovaries, placenta, and the endocrine cells that are a part of each of these tissues; blood vessels, including arteries, veins, capillaries and the cells from these vessels; lung tissue; heart tissue and whole organ; heart valves; liver; kidney; intestines; bone, including osteocyte
  • the present compounds may be administered to a subject orally, topically, transdermally through skin or via the mucosal membrane for example the nasal mucosa and buccal mucosa, or parenterally including intravenous, intramuscular and subcutaneous administration.
  • the compound may be further administered subcutaneously using an oil delivery vehicle for improved uptake and sustained effectiveness.
  • the compositions may be in the form of solid, semi-solid or liquid dosage forms such as for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, patches, creams, gels, or the like preferably in unit dosage forms suitable for single administration of precise dosages.
  • compositions can be formulated using suitable solvents including cyclodextrin, various proteins, oils such as, com oil or sesame oil, or alcohols, the solvents of choice being dependent on the route of administration and the need for sustained delivery.
  • suitable solvents including cyclodextrin, various proteins, oils such as, com oil or sesame oil, or alcohols
  • the solvents of choice being dependent on the route of administration and the need for sustained delivery.
  • intravenous administration of the composition would utilize an aqueous solvent
  • subcutaneous delivery of the composition might utilize an oil solvent.
  • the therapeutic formulations will include a conventional pharmaceutical carrier or excipient and a therapeutically effective amount of the active agent (cytoprotective compound) and in addition, may include for example, other therapeutic agents, carriers, adjuvants.
  • the amount of active compound administered will depend on the human or animal subject being treated, the severity of the condition, the manner of administration and the judgement of the prescribing clinician. Typical compositions contain approximately 0.01-95% by weight of active ingredient with the balance one or more acceptable non-toxic carriers. The percentage of active ingredient will depend upon the dosage form and the mode of administration. Standard formulations have been enumerated in US Patent 6,020,510 (incorporated by reference) and are similarly applicable herein.
  • An effective dose of the active agent as measured in the plasma of a subject may be for example in the range of 5pg/ml-5000pg/ml.
  • Example 1 Method of synthesis of a 17-alkyl ether of 17 ⁇ -estradiol.
  • Analytical reversed-phase high-performance liquid chromatography was performed on a Thermo Separation/SpectraPhysics (Fremont, CA) system consisting of an SP8810 isocratic pump, a Rheodyne (Cotati, CA) Model 7125 injector valve equipped with a 20- ⁇ l sample loop, an SP8450 variable wavelength UV/VIS detector operated at 280 nm, and an SP4290 computing integrator.
  • SP8810 isocratic pump
  • Rheodyne Cotati, CA
  • Model 7125 injector valve equipped with a 20- ⁇ l sample loop
  • an SP8450 variable wavelength UV/VIS detector operated at 280 nm
  • SP4290 computing integrator A 15cm x 4.6 mm id.
  • octadecylsilica column Phase Sep S5 ODS2, Queensferry, Clwyd, UK
  • a mobile phase of acetonitrile containing 1% acetic acid at a flow rate of 1.0 mlVmin were used for the analyses.
  • Cell parameters for each structure were refined using up to 8192 reflections and a hemisphere of data (1381 frames) was collected using the w-scan method (0.3° frame width).
  • the first 50 frames were remeasured at the end of data collection to monitor instrument and crystal stability (maximum correction on I was ⁇ 1 %).
  • Absorption corrections by integration were applied based on measured indexed crystal faces. Both structures were solved by the Direct Methods in SHELXTL5, (Sheldrick, G. M. (1998). SHELXTL5.
  • Benzyl bromide was added to 5 g (18 mmol) of 1 and 10 g (72 mmol) potassium carbonate in 100 ml of acetone 5.7g (4.0mL, 34 mmol). The mixture was refluxed overnight. Upon cooling the solid was removed by filtration. The filtrate was collected and acetone was removed in vacuo leaving behind clear yellowish oil, which solidified on standing. Recrystallization from ethyl acetate/hexane gave 6.1g (93% yield) of a white fluffy solid, m.p.
  • Mouse clonal hippocampal HT-22 cells were cultured in DMEM media supplemented with 10% fetal bovine serum under standard cell culture conditions. All wells in the 96 well culture plate contained approximately 5,000 HT-22 cells as determined by a Neubauer hemacytometer and the cells were incubated for 24 hrs before the compounds were added. The estradiol derivatives were purified recrystallization or column chromatography and were free from (1) as determined by HPLC. All agents were dissolved in absolute ethanol and diluted, with the culture media, to a final concentration of 0.01 ⁇ M; 0.1 ⁇ M; 1.0 ⁇ M; and 10 ⁇ M in their respective wells.
  • the cells were further incubated for 24 hrs before sodium glutamate in a solution of phosphate buffer was added.
  • Cell viability was quantified 2 hrs later by the calcein AM assay (Green, P.S., E.LPerez, T. Calloway and J.W. Simpkins: (2000), Journal of Neurocytology, Vol. 29, pp. 419-423) in a phosphate buffer solution.
  • 4c-f of the six 17 ⁇ -O-alkylestradiols showed improved neuroprotection in a dose-dependent manner against the glutamate- induced oxidative damage in murine HT-22 cells at concentrations of 0.1 ⁇ M and higher (Fig. 4).
  • These compounds were essentially equipotent at 1 ⁇ M (approximately twice as many cells were viable compared to the control), and showed no apparent relationship with a single molecular property such as lipophilicity (based on the calculated log P).
  • log P The logarithm of the 1-octanol/water partition coefficient (log P) was calculated by an atom fragment method implemented in the molecular modeling package HyperChem version 6.0 (Hypercube, Gainesville, FL): Ghose, et al., (1988) J. Comput Chem, Vol. 9, pp. 80-90.
  • the obtained log P values were as follows: 4.01 (1), 4.29 (4a), 4.63 (4b), 5.10 (4c), 5.49 (4d), 6.29 (4e), and 7.08 (4f).
  • the calculated log P for the 3-alkylestradiols were 4.09 (5a), 5.25 (5b), and 6.83 (5c).
  • the butyl (4e) and octyl ether (4f) were neuroprotective to a similar extent at a concentration of 10 ⁇ M and 1 ⁇ M.
  • the parent compound (1) and 17 ⁇ - methylestradiol were effective only at 10 ⁇ M, and were less active then 4c and 4e at this concentration.
  • 17 ⁇ -ethylestradiol (4a) was ineffective even at 10 ⁇ M.
  • the 5(b) and 5c ethers in which the phenolic hydroxyl in the A-ring were blocked were ineffective with respect to cytoprotection.
  • 17 ⁇ and 17 ⁇ -alkyl ethers of estradiol have dose-dependent cytoprotective effects in vitro. Moreover, this effect is manifested at lower concentration ( ⁇ 1 ⁇ M) than that of the parent compound.
  • ER Human cloned estrogen receptors (ER) for both ER ⁇ and ER ⁇ areas were mixed with radiolabeled 17 ⁇ -estradiol and with no other compound (total binding), with excessive amount of diethylstilbesterol (non-specific binding), or with cold (unlabeled) estradiol, or the test compound. All groups were determined in duplicate or triplicate. 17 ⁇ -estradiol was tested at concentrations of 0.1, 1 and 10 M, while all other test compounds were assayed at
  • 17 ⁇ -estradiol produced a dose-dependent inhibition of binding of the labeled estradiol to both receptors with approximately equal affinity.
  • the activity of 17 ⁇ estradiol was assigned a value of 1.
  • Test compounds were compared to the binding inhibition produced by
  • Values of ⁇ 0.1 indicate weak binding (less than 10% of the activity of 17 ⁇ -estradiol.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Toxicology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des procédés et des compositions destinés à réaliser un effet cytoprotecteur par la sélection d'un composé polycyclique avec un groupe de phénol à un extrémité de la molécule et un anneau de carbone à l'autre extrémité, de façon qu'un groupe fonctionnel d'alkyle éther, dans lequel le groupe alkyle a la formule CnH2n+1 (n étant égal à 3 et n'excédant pas 20), soit placé sur l'anneau de carbone. Le composé peut servir à réaliser un effet cytoprotecteur dans des cellules et à retarder le développement d'un état dégénératif chez un sujet souffrant d'une maladie, d'un traumatisme ou du vieillissement.
EP01955052A 2000-06-27 2001-06-27 Composes polycycliques modifies d'alkyle ether ayant un phenol terminal et utilisations pour la protection de cellules Withdrawn EP1294446A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US21407700P 2000-06-27 2000-06-27
US214077P 2000-06-27
PCT/US2001/041170 WO2002000619A2 (fr) 2000-06-27 2001-06-27 Composes polycycliques modifies d'alkyle ether ayant un phenol terminal et utilisations pour la protection de cellules

Publications (1)

Publication Number Publication Date
EP1294446A2 true EP1294446A2 (fr) 2003-03-26

Family

ID=22797680

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01955052A Withdrawn EP1294446A2 (fr) 2000-06-27 2001-06-27 Composes polycycliques modifies d'alkyle ether ayant un phenol terminal et utilisations pour la protection de cellules

Country Status (5)

Country Link
US (1) US20020035100A1 (fr)
EP (1) EP1294446A2 (fr)
AU (1) AU2001277258A1 (fr)
CA (1) CA2413552A1 (fr)
WO (1) WO2002000619A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7304171B2 (en) * 2004-05-27 2007-12-04 Migenix Corp. Compounds and methods for cytoprotection
HUP1100723A2 (en) * 2011-12-28 2013-06-28 Avidin Kft Use of estrogen derivatives for preparing medicament for the treatment of psychiatric diseases

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6319914B1 (en) * 1993-11-05 2001-11-20 Apollo Biopharmaceuticals, Inc. Cytoprotective effect of polycyclic phenolic compounds
US5877169A (en) * 1993-11-05 1999-03-02 University Of Florida Research Foundation, Inc. Methods of treatment of ischemic damage
US6350739B1 (en) * 1999-08-11 2002-02-26 University Of Florida Resarch Foundation, Inc. Methods of prevention and treatment of ischemic damage
US5859001A (en) * 1996-01-11 1999-01-12 University Of Florida Research Foundation, Inc. Neuroprotective effects of polycyclic phenolic compounds
US6197833B1 (en) * 1995-07-24 2001-03-06 Apollo Biopharmaceutics, Inc. Neuroprotective effects of polycyclic phenolic compounds
US5554601A (en) * 1993-11-05 1996-09-10 University Of Florida Methods for neuroprotection
KR100543151B1 (ko) * 1997-01-16 2006-01-20 유니버시티 오브 플로리다 리서치 파운데이션, 인코포레이티드 산화방지제와의 상승적인 상호작용을 통해 폴리시클릭 페놀계화합물의 세포 보호 효과를 증강시키는 조성물
EP1032397A1 (fr) * 1997-11-24 2000-09-06 University Of Florida Research Foundation, Inc. Inhibiteurs de la testosterone et utilisation pour la protection de neurones
US6326365B1 (en) * 1999-07-20 2001-12-04 Apollo Biopharmaceutics, Inc. Methods of prevention and treatment of ischemic damage
US6339078B1 (en) * 1999-07-20 2002-01-15 University Of Florida Research Foundation, Inc. Methods of prevention and treatment of ischemic damage

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0200619A2 *

Also Published As

Publication number Publication date
WO2002000619A2 (fr) 2002-01-03
US20020035100A1 (en) 2002-03-21
AU2001277258A1 (en) 2002-01-08
CA2413552A1 (fr) 2002-01-03
WO2002000619A3 (fr) 2002-08-29

Similar Documents

Publication Publication Date Title
EP1272504B1 (fr) Estratrienes a substitution 8beta-hydrocarbyle utilises comme oestrogenes a action selective
DE69628353T2 (de) Benzopyran enthaltende Verbindungen und deren Prodrugformen
DE60025817T2 (de) Ent-steroide als selektiv wirksame estrogene
EP2953959A1 (fr) 3-sulfamates d' strogènes 16- et 17-deutérés à titre d'agents strogéniques
EP2048126A1 (fr) Dérivés de benzocycloheptanes en tant qu'oestrogènes actifs de manière sélective
EP0728140B1 (fr) Nouveaux steroides avec substituants a proprietes de capture de radicaux, procede pour leur fabrication et produits pharmaceutiques renfermant ces composes
EP1525215B1 (fr) Modulateurs de recepteurs de progesterone presentant une activite antigonadotrope augmentee, destines au controle de fertilite et au traitement hormonal substitutif chez la femme
EP1673093A1 (fr) Utilisation de quinoles steroides dans une therapie de remplacement d'oestrogene
Peters et al. 11. beta.-Nitrate estrane analogs: potent estrogens
DE69910068T2 (de) 17beta-acyl-17alpha-propynyl-11beta-arylsteroide und ihre derivate mit agonistischen oder antagonistischen hormonalen aktivitäten
DE19906159A1 (de) 16-Hydroxyestratriene als selektiv wirksame Estrogene
EP1599493B1 (fr) Sulfamate estra-1,3,5(10)-triene-3-yle 2-substitue a effet antitumeur
US20020035100A1 (en) Alkyl ether modified polycyclic compounds having a terminal phenol and uses for protection of cells
EP1517914B1 (fr) Estratrienes 9-alpha substitues servant d'oestrogenes selectivement actifs
SK12052000A3 (sk) E-2-[4-(4-chlór-1,2-difenyl-but-1-enyl)fenoxy]etanol a farmaceutické prípravky, ktoré ho obsahujú
JPS6355488B2 (fr)
DE60311779T2 (de) Steroidale Chinole als Prodrugs von Antioxidantien
JP4046691B2 (ja) トリシクロ［５．２．１．０▲２▼▲．▼▲６▼］−デク−９−イルキサントゲネートの純粋な立体異性体の製造方法およびそれからなる医薬品
DE69515341T2 (de) Diarylethylen-metallogenderivate, verfahren zu deren herstellung und diese enthaltende arzneizusammensetzungen
EP1636249A1 (fr) Chimiotherapie orientee cible de tumeurs des organes sexuels
DE4434488A1 (de) Steroidester und -amide, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
Peters et al. Analogs of [(triethylsilyl) ethynyl] estradiol as potential antifertility agents
JP2004505093A (ja) １６α−メチルまたはエチル置換エストロゲン
US20020132802A1 (en) Cytoprotective polycyclic compounds
EP1594884B1 (fr) Sulfamates 18a-homoestra-1,3,5(10)-triene-3-yle 2-substitues a effet antitumeur

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030108

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060103